Development of new tools for search and validation of molecular targets for therapy against Plasmodium vivax

Abstract

Malaria caused by Plasmodium vivax is the most widely distributed Malaria form in the world. Worldwide, 2.5 billion people are at risk of Plasmodium vivax infection, with 8.5 million cases worldwide in 2015. Brazil, together with Venezuela, is the leader in cases in the Americas, 99.5% of which are reported in the region called Legal Amazon. Currently more than 85% of cases in Brazil are caused by P. vivax. P. vivax has several unique biological characteristics, such as: exclusive preference for reticulocyte infection, the production of sexual stages (gametocytes) observed in peripheral blood quite early after infection and formation of hypnozoites (a latent stage that remains in the liver). Therefore, the same control measures used for P. falciparum have revealed failures in controlling Vivax Malaria. Presently, P. vivax has been considered a pathogen that causes severe immunopathological symptoms and an increase in the resistance to chloroquine has alarmed the scientific community. Moreover, the impossibility of in vitro cultivation for long periods, along with its particular characteristics, has been challenging the understanding of the biology of this pathogen. In this proposal we intend to identify and characterize potential molecular targets of P. vivax for use in vaccine strategies and for antimalarial treatment. Also, we wish to verify the participation of molecules involved in endothelial disorders and evaluate potential inhibitors. More specifically, and considering the development of antimalarials, we intend through in silico analysis to identify kinases (mainly) as molecular targets of P. vivax and establish a technological platform for the discovery of new drugs taking into account all stages of the parasite, including hypnozoites, in which we aim to work with the recently established National Hypnozoite Research Center (FIOCRUZ-RJ), that provides models of non-human primates and infection with P. cynomolgi that will be used to evaluate both drugs and experimental vaccines generated in the previous steps. Also, by means of new-generation sequencing of the entire P. vivax transcriptome (RNA-seq) and integrated data analysis, we hope to track new targets that have not yet been considered in pre-existing databases. Finally, we intend to evaluate plasma factors of infected patients capable of interfering in endothelial functions, as well as to test specific inhibitors in a model of murine infection capable of inducing immunopathological complications. (AU)